Prenatal Extracellular Vesicles and Steroid Hormones as Biological Mechanisms Underlying Gestational Factors Associated with Neurodevelopmental Risk

产前细胞外囊泡和类固醇激素作为与神经发育风险相关的妊娠因素的生物机制

• 批准号: 10739066
• 负责人: Morgan Firestein
• 金额: $ 13.08万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739066
• 关键词: Address; Age Months; Amniotic Fluid; Androstenedione; Award; Basic Science; Biological; Biological Markers; Biometry; Brain; Cells; Child; Clinical Psychology; Clinical Research; Cohort Studies; Communication; Data; Development; Diagnosis; Disease; Early Intervention; Early identification; Emotional; Endocrinology; Enzyme-Linked Immunosorbent Assay; Functional disorder; Gene Expression Regulation; Gestational Diabetes; Goals; Health; Hydroxyprogesterone; Hypertension; Individual; Infant; Interdisciplinary Study; Lead; Lifestyle-related condition; Longitudinal Studies; Mammalian Cell; Mass Spectrum Analysis; Measurement; Measures; Mediating; Mediation; Metabolic; MicroRNAs; Molecular Biology; Motor; Neurodevelopmental Deficit; Neurodevelopmental Disorder; Outcome; Parents; Pathway interactions; Perinatal; Physiology; Plasma; Pregnancy; Pregnant Women; Progesterone; Proteins; Psychiatry; Quality of life; RNA; Reporting; Research; Research Design; Risk; Risk Factors; Role; Source; Steroid biosynthesis; Steroids; Testosterone; Toddler; Training; Transcriptional Regulation; Translational Research; Up-Regulation; Woman; autism spectrum disorder; career; cohort; design; epidemiology study; extracellular vesicles; fetal; fetal blood; longitudinal dataset; motor deficit; neurobehavioral; neurodevelopment; neuropsychiatry; offspring; postnatal; pregnancy disorder; prenatal; programs; recruit; service intervention; skills; social; statistics; steroid hormone; tool; translational research program

Project Summary/Abstract The applicant's career goal is to lead a multidisciplinary research program that will investigate a network of perinatal pathways through which maternal, fetal, and placental physiology impacts fetal brain development and risk for neurodevelopmental disorders, including autism spectrum disorder (ASD). The research will implement translational and clinical research approaches to uncover early-emerging biomarkers that may serve as tools for early identification of at-risk children. To effectively establish and lead this research program, intensive training in longitudinal study design, molecular biology, endocrinology, clinical psychology/psychiatry, and statistics is required. The K99 study aims to address a crucial gap by evaluating the independent and interactive effects of prenatal maternal/fetal EVs and maternal/fetal steroid hormones as potential biological mechanisms underlying infant neurobehavioral and social-emotional development. Postnatally, elevated EV- associated protein (EV-AP) levels and upregulation of EV microRNAs (miRNAs) have been observed in individuals with neuropsychiatric conditions including ASD. However, no prior studies have evaluated the relationship between prenatal maternal/fetal EV-AP levels and later child neurodevelopment. It has also been shown that higher levels of the Δ4 steroid hormones (progesterone, 17α-hydroxy-progesterone, androstenedione and testosterone) in amniotic fluid are associated with greater ASD-related behaviors. Therefore, aberrant levels of both EVs and steroid hormones have been implicated in ASD pathophysiology. The proposed K99 study will use biological data (maternal/fetal EVs, maternal/fetal steroid hormones) and data obtained through neurodevelopmental assessments as part of a large, longitudinal pregnancy cohort study to determine the interactive effect of elevated EV-AP levels and elevated levels of the Δ4 steroids on infant neurobehavioral and social-emotional development. Elevated levels of EV-AP and Δ4 steroid hormones have also been observed in women diagnosed with a hypertensive disorder of pregnancy or gestational diabetes mellitus, conditions that are associated with increased neurodevelopmental risk in offspring, suggesting that these biological mechanisms may mediate the neurodevelopment risk associated with these gestational conditions. The R00 study will involve a moderated mediation analysis to evaluate whether the level of EV-APs and Δ4 steroids contributes to the observed association between hypertensive disorders of pregnancy/gestational diabetes mellitus and offspring neurobehavioral and social-emotional development. This approach will elucidate new biological mechanisms underlying neurobehavioral development and may provide important tools to identify children in need of early intervention services.

项目摘要/摘要 申请人的职业目标是领导一项多学科研究计划，该计划将调查 围产期途径通过这些途径，胎儿，胎儿和胎盘生理影响胎儿脑发育 和神经发育障碍的风险，包括自闭症谱系障碍（ASD）。研究将 实施翻译和临床研究方法，以发现可能的早期生物标志物 用作早日识别高危儿童的工具。为了有效建立和领导该研究计划， 纵向研究设计，分子生物学，内分泌学，临床心理学/精神病学的强化培训， 和统计是必需的。 K99研究旨在通过评估独立和 产前母亲/胎儿电动汽车和母体/胎儿立体激素作为潜在生物学的互动效应 婴儿神经行为和社会情感发展的基础机制。产后，EV-升高 在 患有神经精神病患者，包括ASD。但是，没有先前的研究评估 产前孕产妇/胎儿EV-AP水平与后来儿童神经发育之间的关系。也一直 表明较高水平的Δ4类固醇骑马（孕酮，17α-羟基胃酮， 羊水中的雄性二酮和睾丸激素与更大的ASD相关行为有关。 因此，在ASD病理生理学中，已经暗示了EVS和类固醇激素的异常水平。 拟议的K99研究将使用生物学数据（母亲/胎儿电动汽车，母体/胎儿类固醇激素）和数据 通过神经发育评估获得的，作为大型纵向怀孕队列研究的一部分 确定升高的EV-AP水平和Δ4立体的水平升高对婴儿的互动效果 神经行为和社会情感发展。 EV-AP和Δ4类固醇激素的水平升高具有 在被诊断出患有妊娠或妊娠糖尿病高血压疾病的妇女中也观察到 Mellitus，与后代神经发育风险增加有关的疾病，表明 这些生物学机制可能介导与这些妊娠有关的神经发育风险 状况。 R00研究将涉及调解分析，以评估EV-APS的水平是否水平 Δ4类固醇有助于观察到的高血压疾病的关联 怀孕/妊娠糖尿病和后代神经行为和社会情感发展。这 方法将阐明神经行为发展的新生物学机制，并可能提供 确定需要早期干预服务的儿童的重要工具。